CN104971061A - Novel application of rifamycin-nitroimidazole coupling molecule - Google Patents
Novel application of rifamycin-nitroimidazole coupling molecule Download PDFInfo
- Publication number
- CN104971061A CN104971061A CN201510313301.4A CN201510313301A CN104971061A CN 104971061 A CN104971061 A CN 104971061A CN 201510313301 A CN201510313301 A CN 201510313301A CN 104971061 A CN104971061 A CN 104971061A
- Authority
- CN
- China
- Prior art keywords
- rifamycin
- metronidazole
- coupling molecule
- nitroimidazole coupling
- rifampicin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a novel application of rifamycin-nitroimidazole coupling molecule and belongs to the field of medicinal chemistry. The rifamycin-nitroimidazole coupling molecule shows high activity to drug-resistant strains in the treatment of undistinguishable Clostridium, Helicobacter pylori infection related diseases, not only has antibacterial resistant activity to the rifamycin single drug-resistance bacteria and metronidazole single drug-resistance bacteria, but also has antibacterial activity against rifamycin resistant and metronidazole double drug-resistance bacteria; and the activity of the coupling molecule is superior to that of the composition of rifampicin and metronidazole in the molar ratio of 1:1.
Description
Technical field
The invention belongs to medicinal chemistry arts, particularly relate to the novelty teabag of a kind of rifamycin-nitroimidazole coupling molecule.
Background technology
In US Patent No. 7,678, the antimicrobial compound 4-deoxidation-3 being in development is disclosed in 791 B2,4-[2-volution-[2-(2-methyl-5-nitro-imidazoles-1-base) ethyl]-piperidin-4-yl]]-(1 hydrogen)-imidazo-(2,5-dihydro) rifamycin-S and rifamycin-nitroimidazole coupling molecule, it all has antibacterial activity to rifamycin list Resistant strain and metronidazole list Resistant strain, shows its dual-target characteristic.But, from its structure activity relationship and theory speculates, its to the activity of the two Resistant strain of rifamycin and metronidazole should with the 1:1 molar mixture of rifamycin (rifampicin) and metronidazole quite, not or only have faint antibacterial activity.
Rifamycin antibiotic is the class antibiotic produced by Mediterranean Streptothrix, and it has broad-spectrum antibacterial action, all very strong to the effect of the gram positive bacterias, particularly drug-resistant S. aureus such as tubercule bacillus, leprosy bacillus, streptococcus, streptococcus pneumoniae.
Metronidazole has powerful antibacterial action to most of anaerobe, but to aerobe and facultative anaerobe without effect, antimicrobial spectrum comprises fusiform bacilarmature, aerogenesis clostridium etc., is mainly used in treatment or the microbial local infection of prevention anaerobism.
Helicobacter pylori (Helicobacter pylori, Hp) be a kind of micro-oxygen gram negative bacteria, it is the main cause that peptic ulcer occurs and recurs, it is reported Hp eradicate after the year relapse rate of Peptic Ulcers be 6.54%, the Hp positive Peptic Ulcers year relapse rate up to 23.33%, therefore eradicate Hp to control ulcer recurrence very important.But in recent years along with the extensive use of antibiotic in Hp treatment of infection, the resistance problems of Hp is day by day serious, in the urgent need to the effective new drug of drug resistance helicobacter pylori.
Clestridium difficile (Clostridium difficile, CD) be a kind of positive bacillus cereus of Gram's staining of anaerobism, be distributed widely in the feces of natural environment and animal and human, Clestridium difficile can produce toxin A and toxin B, cause cytopathy after invading intestinal mucosa, cause a series of infection related clinical manifestations.Brood body can be very fast dead as being exposed in air, but spore resistance is comparatively strong, resistance to drying, heat-resisting and can resist multiple disinfectant, can in hospital environment and medical worker at least survival 6 months on hand.Clestridium difficile has the trend of Outbreak this year, effective in the urgent need to infecting Clestridium difficile, particularly can overcome the new drug of drug resistance.
Drug resistance tuberculosis develops rapidly in recent years, the particularly appearance of Drug-fast case (MDR-TB) and wide spectrum drug resistance tuberculosis (XDR-TB), serious challenge is proposed, in the urgent need to treating the antibacterial new drug of drug resistance tuberculosis to the treatment of tuberculosis (TB).
Summary of the invention
In view of the defect that above-mentioned prior art exists, the object of the invention is the novelty teabag proposing a kind of rifamycin-nitroimidazole coupling molecule.
Object of the present invention will be achieved by the following technical programs:
A novelty teabag for rifamycin-nitroimidazole coupling molecule, the structure of described rifamycin-nitroimidazole coupling molecule as formula I, wherein, the described rifamycin-application of nitroimidazole coupling molecule in the medicine preparing antimicrobial agent;
According to the novelty teabag of above-mentioned a kind of rifamycin-nitroimidazole coupling molecule, wherein, described antimicrobial agent comprises anti-rifamycin list fastbacteria, anti-metronidazole list fastbacteria or anti-rifamycin and the two fastbacteria of metronidazole.
According to the novelty teabag of above-mentioned a kind of rifamycin-nitroimidazole coupling molecule, wherein, described antimicrobial agent is the Clestridium difficile of the two drug resistance of the Clestridium difficile of anti-rifamycin list drug resistance, the Clestridium difficile of anti-metronidazole list drug resistance or anti-rifamycin and metronidazole.
According to the novelty teabag of above-mentioned a kind of rifamycin-nitroimidazole coupling molecule, wherein, described antimicrobial agent is the helicobacter pylori of the two drug resistance of the helicobacter pylori of anti-rifamycin list drug resistance, the helicobacter pylori of anti-metronidazole list drug resistance or anti-rifamycin and metronidazole.
Outstanding effect of the present invention is: a kind of rifamycin-nitroimidazole coupling molecule of the present invention prepares the novelty teabag in the medicine of anti-rifamycin and the two fastbacteria of metronidazole at treatment drug resistant infection, not only all there is antibacterial activity to rifamycin list Resistant strain and metronidazole list Resistant strain, and to rifamycin and the two Resistant strain of metronidazole, there is strong antibacterial action.The antibacterial activity that described rifamycin-nitroimidazole coupling molecule is comparatively used alone rifampicin, metronidazole or medication of rifampicin and metronidazole 1:1 mol ratio being joined together to the antibacterial activity that Gram-positive anaerobism produces malicious type pathogen Clestridium difficile is strong; The antibacterial activity of rifampicin, metronidazole or medication of rifampicin and metronidazole 1:1 mol ratio being joined together comparatively is used alone to micro-oxygen Gram-negative gastrointestinal tract pathogen-helicobacter pylori antibacterial activity strong simultaneously.The antibacterial activity that rifamycin-nitroimidazole coupling molecule produces malicious type pathogen Clestridium difficile to Gram-positive anaerobism and the rifamycin pharmacophore micro-oxygen Gram-negative gastrointestinal tract pathogen-helicobacter pylori antibacterial activity mainly come from coupling molecule, but the metronidazole pharmacophore in molecule also can contribute secondary antibacterial activity.
Below just the specific embodiment of the present invention is described in further detail in conjunction with the embodiments, is easier to make technical solution of the present invention understand, grasp.
Detailed description of the invention
Below by specific embodiment, method of the present invention is described, but the present invention is not limited thereto.Experimental technique described in following embodiment, if no special instructions, is conventional method; Described reagent and material, if no special instructions, all can obtain from commercial channels.
Embodiment 1 one kinds of rifamycins-nitroimidazole coupling molecule is to the antibacterial activity of helicobacter pylori
1.1 materials and methods
1.1.1 the selection of bacterial strain
ATCC#700392 (CB1531) is wild type strain, buys from American Type Culture Collecti (AmericanType Culture Collection, ATCC, Manassas, Virginia).CB1573, CB1609, CB1610, CB1612, CB1613, CB1614, CB1771, CB1893, CB1894, CB1900, CB1901, CB1902, CB1903, CB1993 be from CB1531 obtain etc. gene mutation bacterial strain, carry specific drug resistant gene, above-mentioned bacterial strains is provided by red promise medicine.Bacterial strain describes and refers to table 1.
Table 1 inoculation in the TSAII culture medium of not drug containing derives from the strains of glycerol stocks
1.1.2 the configuration of culture medium
According to Clinical Laboratory Standard association guide (Clinical Laboratory Standards Instituteguideline, CLSI) M7-A7 (By Dilution aerobe to antibacterial Antimicrobial Susceptibility Testing Methodologies, the standard of approval) preparation.Cation is adopted to regulate and the MuellerHinton agar (MHII) containing 5% (v/v) ageing sheep serum carries out the dilution of tested material.The cellar culture of helicobacter pylori then adopts the cruel peptone soy agar (TSAII) of pancreas containing 5% (v/v) sheep serum.
1.1.3 the configuration of test medicine
Rifamycin-nitroimidazole coupling molecule (Lot#DJ-001-042-1), rifampicin (Sigma, Cat#R-3501), metronidazole (Sigma, and clarithromycin (Sigma, Cat#C-9742) Simultaneously test Cat#M-3761).
Antibacterials stock solution adopts pressed powder preparation, and is stored in-20 DEG C of refrigerators immediately, the longest for one month.For ensureing that agar dilution measures the repeatability of MIC test, adopt the QC reference agent clarithromycin of CLSI to measure, to issue with CLSI and the accepted quality control clearance upgraded compares simultaneously.
Clarithromycin, rifamycin-nitroimidazole coupling molecule, metronidazole and rifampicin is dissolved in the DMSO of 100%.Clarithromycin and metronidazole are colourless transparent solution when 6.4mg/mL concentration, in orange red under rifampicin 6.4mg/mL concentration, rifamycin-nitroimidazole coupling molecule is red in royal purple under 6.4mg/mL concentration, the rifampicin of mol ratio 1:1 and metronidazole mixture employing 16.4mg rifampicin (molecular weight 822) add 3.4mg metronidazole (molecular weight 171) and are suspended in 2mL DMSO formulated, and mixture solution is orange red.All tested materials are all easily molten in appointment solvent, simple mixing and get final product.
1.1.4 agar preparation
Agar (being cooled to 55 DEG C in a water bath) and 0.1 part of antibacterials stock solution diluting (100 times) in advance of 9.9mL fusing is added in single disposable sterilized test tube, mixing, inject the sterile petri dish (60mm × 15mm, Cat#08-772B) of suitable size immediately.Above device contributes to mix homogeneously, and can prevent because cooling the part agar solidification caused.Test slab agar dilution scheme is see table 2, and the program and easy, can obtain again the high result of repeatability.Wherein, the actual dilution range of often kind of medicine is: rifampicin=0.03-32mg/L; Metronidazole=0.03-32mg/L; Rifampicin+metronidazole (1:1M)=0.03-32mg/L; Clarithromycin=0.008-0.25mg/L; Rifamycin-nitroimidazole coupling molecule=0.002-32mg/L.
Table 2 test slab agar dilution scheme
1.1.5 culture dish prepares
This test adopts 6cm culture dish to carry out, and adds 10mL agar culture medium and antibacterials in culture dish.Tested antibacterials adopt preceding method analysis to be diluted to suitable concentration, obtain a series of 100 times of concentration and for the intermediate concentration storing solution of 2 times of dilution methods, often kind of intermediate concentration storing solution is drawn 0.1mL and is added in the agar of 10mL fusing (seeing above), be inverted mixing, and be poured into immediately in sterile petri dish.According to said method, be equivalent to antibacterials to dilute by 1:100, the ultimate density of diluent is 1%.Prepare 2 not containing the contrast culture dish of antibacterials, for growth control simultaneously.Culture dish at room temperature natural drying remains to surperficial no liquid, used, or keep in Dark Place to use at 4 DEG C on the same day.Above bacterial strain, in the micro-oxygen environment being suitable for pylori, hatches 5 days for 35-37 DEG C.
1.1.6 inoculate:
Test culture dish is commercially available.Adopt the middle bacterium colony cultivating 120 hours (5 days) of method (TSA+5% Sheep Blood) above to prepare 5mL meat soup inoculum, this concentration inoculum is at O.D.
600to be 0.013 (be equivalent to containing 8 × 10 absorbance
6cFU/mL).Each inoculum 0.2mL pipet mixes 15 times, adopts the pipet (multichannel or single channel) through calibration, draws (8 × 10 of the adjusted cell concentration of 0.002ml
6cFU/mL) cell suspension adds to agar plates surface, and final inoculum concentration is equivalent to about 2 × 10
4cFU/ point.First inoculate first not containing the contrast culture dish of antibacterials, then from the culture dish containing least concentration antibacterials, inoculate remaining culture dish.Liquid-transfering sucker is changed when inoculating different medicine groups.Finally inoculate second not containing the contrast culture dish of antibacterials, thus do not occur in guarantee test process to pollute or obvious drug residue.
Hatch: in the micro-oxygen environment being suitable for pylori, hatch 5 days for 35-37 DEG C.
Data notes: MIC value is the minimum serial dilution antibacterials concentration of anti-bacteria visible growth, does not consider the muddiness that inoculum is residual or single bacterium colony.The result of reference agent (as clarithromycin) is at tolerance interval (QC=0.015-0.12) and the MIC value of testing compound (rifampicin, metronidazole and rifamycin-nitroimidazole coupling molecule) then thinks that this result of the test is reliable in 2 two times of method dilution range.
Adopt micro-oxygen bacterio-agar method measure rifamycin-nitroimidazole coupling molecule and control drug rifampicin, metronidazole and standard care medicine clarithromycin to one group with metronidazole, rifampicin or fluoroquinolones drug resistance etc. the minimum inhibitory concentration (MIC) of gene helicobacter pylori (Helicobacter pylori).MIC measures and adopts the cation containing 5% ageing sheep serum to regulate Mueller Hinton agar, and preparation method is with reference to clinical laboratory Standards Institution guide (Clinical Laboratory Standards Institute guideline) M11-A6 part.All tests are all cultivated 5 days under 35-37 DEG C of micro-aerobic environment of applicable spiral Pseudomonas growth.Experimental result is in table 3.
Table 3 agar method measure rifamycin-nitroimidazole coupling molecule, clarithromycin, metronidazole and rifampicin to carry rifamycin, nitroimidazole and quinolone resistance mutation etc. the MIC value of gene helicobacter pylorus strain
Note: RIF+MET (1:1M) represents rifampicin and the metronidazole mixture of mol ratio 1:1.
Result shows, rifamycin-nitroimidazole coupling molecule is to helicobacter pylori type strain (ATCC#700392, CB1531) MIC is≤0.002mg/L, and activity is obviously better than rifampicin (0.5mg/L) and metronidazole (2mg/L).For the rifamycin Resistant strain with rpoB sudden change, the MIC value of rifamycin-nitroimidazole coupling molecule increases 8-250 doubly, and rifampicin MIC value increases >=64 times; For the metronidazole Resistant strain having rdxA (rdxAR16S) and suddenly change, the MIC value of metronidazole is increased to 32mg/L (suitable activity decrease 16 times), and the bacteriostatic activity of rifamycin-nitroimidazole coupling molecule has no obvious reduction.Therefore, the helicobacter pylori bacteriostatic activity result of single drug resistance shows, rifamycin-nitroimidazole coupling molecule is all better than two parent antibiotic in its molecular structure.
Rifamycin-nitroimidazole coupling molecule is to having height rifamycin medicament-resistant mutation (as rpoBL525I, D530N) the helicobacter pylori bacteriostatic activity of metronidazole medicament-resistant mutation (rdxAR16S) or rdxAE75stop nonsense mutation is merged, with it to only having rpoBL525I, helicobacter pylori (CB1614) activity of D530N single mutation compares decline 4 times.This result shows, rifamycin-nitroimidazole coupling molecule mainly comes from the rifamycin pharmacophore in molecule for the activity of the micro-oxygen gastrointestinal tract pathogen-helicobacter pylori of Gram-negative, the metronidazole pharmacophore simultaneously in its molecule also contributes part antibacterial activity.Further research shows, rifamycin-nitroimidazole coupling molecule and rifampicin: compared with metronidazole (1:1M) mixture, 250 times are exceeded to wild-type strain activity, to there is the high 16-533 of activity of rifamycin list Resistant strain doubly, active high 125 times to having metronidazole list Resistant strain, to rifamycin and the two Resistant strain activity of metronidazole high >=64 times.The antibacterial activity of rifamycin-nitroimidazole coupling molecule is not by the impact of current ubiquitous mediated quinolone resistance sudden change.
This result of the test prompting rifamycin-nitroimidazole coupling molecule mainly comes from the rifamycin pharmacophore in coupling molecule for the activity of micro-oxygen Gram-negative gastrointestinal tract pathogen-helicobacter pylori, the metronidazole pharmacophore simultaneously in its molecule also provides secondary antibacterial activity.
Embodiment 2 one kinds of rifamycins-nitroimidazole coupling molecule produces the antibacterial activity of malicious type pathogen Clestridium difficile to Gram-positive anaerobism
2.1 materials and methods
2.1.1 the selection of bacterial strain
ATCC#BAA-1382 (CB1921), for producing malicious type Clestridium difficile, buys from American Type Culture Collecti (American Type Culture Collection, ATCC, Manassas, Virginia).CB1934, CB1939, CB1940, CB1941, CB1942 be from CB1921 obtain carry specific medicament-resistant mutation etc. gene bacterial strain.This test strain provides by red promise medicine.Bacterial strain describes and refers to table 4.Table 4 inoculation in the supplement type brucella agar culture medium of not drug containing derives from the strains of glycerol stocks
*note: the gene Resistant strains such as CB1939 confirm without order-checking, but CB1942 is the lineal descent of CB1939, illustrates the one sudden change at least existed in gyrA (D71Y) or (T82A).
2.1.2 the configuration of culture medium
According to Clinical Laboratory Standard association guide M7-A7 (By Dilution aerobe to antibacterial Antimicrobial Susceptibility Testing Methodologies, the standard of approval) preparation.Clestridium difficile adopts the brucella agar (brucella broth basis, agar, 10mg/L vitamin K1,5mg/L haemachrome, 5% (w/v) sheep serum) supplemented.
2.1.3 test medicine storage and dilution
Rifamycin-nitroimidazole coupling molecule (lot#DJ-001-042-1), rifampicin (Sigma, Cat#R-3501), metronidazole (Sigma, and vancomycin (Sigma, Cat#861987) Simultaneously test Cat#M-3761).
Antibacterials stock solution adopts pressed powder preparation, and is stored in-20 DEG C of refrigerators immediately, the longest for one month.For ensureing that agar dilution measures the repeatability of MIC test, adopt the QC reference agent vancomycin of CSLI to measure, to issue with CLSI and the accepted quality control clearance upgraded compares simultaneously.
Vancomycin is dissolved in 10mg/mL sterilized water, and filters with 0.2 μm of injection filter.Rifamycin-nitroimidazole coupling molecule, metronidazole and rifampicin is dissolved in the DMSO of 100%.Vancomycin and metronidazole are colourless transparent solution when 6.4mg/mL concentration, in orange red under rifampicin 6.4mg/mL concentration, rifamycin-nitroimidazole coupling molecule is red in royal purple under 6.4mg/mL concentration, the rifampicin of mol ratio 1:1 and metronidazole mixture employing 16.4mg rifampicin (molecular weight 822) add 3.4mg metronidazole (molecular weight 171) and are suspended in 2mL DMSO formulated, and mixture solution is orange red.All tested materials are all easily molten in appointment solvent, simple mixing and get final product.
2.1.4 agar preparation (specifically see 1.1.4 and table 2)
The actual dilution range of often kind of medicine is: rifampicin=0.03-32mg/L; Metronidazole=0.03-32mg/L; Rifampicin+metronidazole (1:1M)=0.03-32mg/L; Vancomycin=0.25-8mg/L; Rifamycin-nitroimidazole coupling molecule=0.002-32mg/L.
2.1.5 culture dish prepares (detailed step is see 1.1.5)
2.1.6 inoculate:
First test culture dish is numbered.Adopt the bacterium colony cultivating 72 hours (3 days) in method above under oxygen free condition to prepare 5mL MHII meat soup inoculum, this concentration inoculum is at O.D.
600to be 0.013 (be equivalent to containing 1 × 10 absorbance
7cFU/mL).Each inoculum 0.2mL pipet mixing>=5 times, adopts the pipet (multichannel or single channel) through calibration, draws (10 of the adjusted cell concentration of 0.002ml
7cFU/mL) cell suspension adds to agar plates surface, and final inoculum concentration is equivalent to about 2 × 10
4cFU/ point.First inoculate first not containing the contrast culture dish of antibacterials, then from the culture dish containing least concentration antibacterials, inoculate remaining culture dish.Liquid-transfering sucker is changed when inoculating different medicine groups.Finally inoculate second not containing the contrast culture dish of antibacterials, thus do not occur in guarantee test process to pollute or obvious drug residue.
Hatch: containing in the oxygen-free seal storehouse environment formed by gas generator of methylene blue indicator, hatch 3 days for 35-37 DEG C.
Data notes: MIC value is the minimum serial dilution antibacterials concentration of anti-bacteria visible growth, does not consider the muddiness that inoculum is residual or single bacterium colony.The result of reference agent (as vancomycin) is at tolerance interval (QC=0.5-4mg/L) and the MIC value of testing compound (as vancomycin and rifamycin-nitroimidazole coupling molecule) then thinks that this result of the test is reliable in 2 two times of method dilution range.Experimental result is in table 5.
Table 5 agar method measure rifamycin-nitroimidazole coupling molecule, rifampicin, metronidazole and vancomycin to carry rifamycin or quinolone resistance mutation etc. the MIC value of gene helicobacter pylorus strain
Experimental result shows, the result of vancomycin matched group is consistent with expection, and MIC is 1-4mg/L, and two times, these value≤2 method dilution range meets the tolerance interval of CLSI QC, the MIC value of this test determination is described reliably.
Rifamycin-nitroimidazole coupling molecule is to Clestridium difficile (BAA1392, CB1921) very strong bacteriostasis is had, MIC≤0.002mg/L, its active close with rifampicin (MIC≤0.03mg/L), is better than metronidazole (MIC=0.25mg/L) and vancomycin (MIC=1 or 4mg/L).
For the rifamycin Resistant strain (CB1934, CB1940, CB1942) of carrying rpoB (Q489K) and suddenling change, the bacteriostatic activity of rifamycin-nitroimidazole coupling molecule is affected (MIC value increase >=30-250 doubly), but still keep very high activity (as MIC=0.06or 0.5mg/L), and be greatly better than rifampicin, rifampicin also cannot observe any In Vitro Bacteriostatic (32mg/L, MIC increase >=1066 times) under maximum concentration.Relative to CB1934 (carrying the rifamycin list Resistant strain that rpoB (Q489K) suddenlys change) and CB1940 (carrying the mediated quinolone resistance bacterial strain of rifamycin drug resistance that rpoB (Q489K) suddenlys change and another kind of different mutation mechanism), CB1942 (carrying rifamycin and quinolinones height medicament-resistant mutation rpoB (Q489K) and gyrA (D71Y, T82A)) is more responsive to rifamycin-nitroimidazole coupling molecule.This mechanism to the enhancing of many Resistant strains antibacterial activity is still bright true, but data have good repeatability in twice test carried out.Mediated quinolone resistance sudden change is there is in the bacterial strains such as CB1939, CB1940 and CB1942, but the activity of rifamycin-nitroimidazole coupling molecule does not affect by mediated quinolone resistance, the mechanism of action (dual-target) of this and rifamycin-nitroimidazole coupling molecule is completely the same.The rifamycin repeatedly carried out-nitroimidazole coupling molecule and vancomycin bacteriostatic test show that the MIC value repeatability of this test is very good.
Table 6 agar method measure rifampicin+metronidazole mixture (1:1 mol ratio) and vancomycin to carry rifamycin or quinolone resistance mutation etc. the MIC value of gene helicobacter pylorus strain
Note: RIF+MET (1:1M) represents rifampicin+metronidazole mixture (1:1 mol ratio)
In a word, no matter to carry wild type ropB wait gene bacterial strain (as CB1921, CB1939 or CB1941) or to carry rifamycin medicament-resistant mutation (rpoBQ489K) etc. gene bacterial strain (as CB1934, CB1940 or CB1942), the antibacterial activity of rifamycin-nitroimidazole coupling molecule be equal to or 4 times be better than rifampicin and metronidazole mixture (1:1 mol ratio) in table 6.
The result of this test shows, rifamycin-nitroimidazole coupling molecule mainly comes from the rifamycin pharmacophore in coupling molecule to the antibacterial activity that Gram-positive anaerobism produces malicious type pathogen Clestridium difficile, but the metronidazole pharmacophore in molecule also can contribute secondary antibacterial activity.
In sum, a kind of rifamycin-nitroimidazole coupling molecule antibacterial activity of being comparatively used alone rifampicin, metronidazole or medication of rifampicin and metronidazole being joined together to the antibacterial activity that Gram-positive anaerobism produces malicious type pathogen Clestridium difficile is strong; The antibacterial activity of rifampicin, metronidazole or medication of rifampicin and metronidazole being joined together comparatively is used alone to micro-oxygen Gram-negative gastrointestinal tract pathogen-helicobacter pylori antibacterial activity strong simultaneously.The antibacterial activity that described rifamycin-nitroimidazole coupling molecule produces malicious type pathogen Clestridium difficile to Gram-positive anaerobism and the rifamycin pharmacophore micro-oxygen Gram-negative gastrointestinal tract pathogen-helicobacter pylori antibacterial activity mainly come from coupling molecule, but the metronidazole pharmacophore in molecule also can contribute secondary antibacterial activity.
The present invention still has numerous embodiments, all employing equivalents or equivalent transformation and all technical schemes formed, and all drops within protection scope of the present invention.
Claims (4)
1. a novelty teabag for rifamycin-nitroimidazole coupling molecule, the structure of described rifamycin-nitroimidazole coupling molecule is characterized in that as formula I, the described rifamycin-application of nitroimidazole coupling molecule in the medicine preparing antimicrobial agent;
2. the novelty teabag of a kind of rifamycin-nitroimidazole coupling molecule according to claim 1, is characterized in that, described antimicrobial agent comprises anti-rifamycin list fastbacteria, anti-metronidazole list fastbacteria or anti-rifamycin and the two fastbacteria of metronidazole.
3. the novelty teabag of a kind of rifamycin-nitroimidazole coupling molecule according to claim 2, it is characterized in that, described antimicrobial agent is the Clestridium difficile of the two drug resistance of the Clestridium difficile of anti-rifamycin list drug resistance, the Clestridium difficile of anti-metronidazole list drug resistance or anti-rifamycin and metronidazole.
4. the novelty teabag of a kind of rifamycin-nitroimidazole coupling molecule according to claim 2, it is characterized in that, described antimicrobial agent is the helicobacter pylori of the two drug resistance of the helicobacter pylori of anti-rifamycin list drug resistance, the helicobacter pylori of anti-metronidazole list drug resistance or anti-rifamycin and metronidazole.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510313301.4A CN104971061B (en) | 2015-06-09 | 2015-06-09 | A kind of purposes of rifamycin nitroimidazole coupling molecule |
| HK16103194.0A HK1215178A1 (en) | 2015-06-09 | 2016-03-18 | New use of a rifamycin nitroimidazole hybrid molecule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510313301.4A CN104971061B (en) | 2015-06-09 | 2015-06-09 | A kind of purposes of rifamycin nitroimidazole coupling molecule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104971061A true CN104971061A (en) | 2015-10-14 |
| CN104971061B CN104971061B (en) | 2017-11-07 |
Family
ID=54268383
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510313301.4A Active CN104971061B (en) | 2015-06-09 | 2015-06-09 | A kind of purposes of rifamycin nitroimidazole coupling molecule |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN104971061B (en) |
| HK (1) | HK1215178A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106822119A (en) * | 2017-02-28 | 2017-06-13 | 丹诺医药(苏州）有限公司 | A kind of new application of rifamycin nitroimidazole coupling molecule |
| CN108047250A (en) * | 2018-02-12 | 2018-05-18 | 丹诺医药(苏州）有限公司 | A kind of application of rifamycin-nitroimidazole coupling molecule |
| WO2018157750A1 (en) * | 2017-02-28 | 2018-09-07 | 丹诺医药(苏州）有限公司 | New applications of rifamycin-nitroimidazole coupling molecules |
| CN109464673A (en) * | 2019-01-08 | 2019-03-15 | 丹诺医药(苏州）有限公司 | Application and the preparation of rifamycin-quinolizine ketone coupling molecule and its salt |
| WO2024036578A1 (en) * | 2022-08-18 | 2024-02-22 | Tennor Therapeutics (Suzhou) Limited | Methods for preventing or treating h. pylori infection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080139577A1 (en) * | 2006-07-12 | 2008-06-12 | Cumbre Pharmaceuticals Inc. | Nitroheteroaryl-containing rifamycin derivatives |
| CN103360370A (en) * | 2012-04-06 | 2013-10-23 | 南京大学 | Synthesis of nitroimidazole derivatives and application of nitroimidazole derivatives in field of antibacterial drugs |
| CN104086534A (en) * | 2014-07-29 | 2014-10-08 | 西南大学 | Quinolone azole alcohol compounds as well as preparation method and application thereof |
-
2015
- 2015-06-09 CN CN201510313301.4A patent/CN104971061B/en active Active
-
2016
- 2016-03-18 HK HK16103194.0A patent/HK1215178A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080139577A1 (en) * | 2006-07-12 | 2008-06-12 | Cumbre Pharmaceuticals Inc. | Nitroheteroaryl-containing rifamycin derivatives |
| CN103360370A (en) * | 2012-04-06 | 2013-10-23 | 南京大学 | Synthesis of nitroimidazole derivatives and application of nitroimidazole derivatives in field of antibacterial drugs |
| CN104086534A (en) * | 2014-07-29 | 2014-10-08 | 西南大学 | Quinolone azole alcohol compounds as well as preparation method and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106822119A (en) * | 2017-02-28 | 2017-06-13 | 丹诺医药(苏州）有限公司 | A kind of new application of rifamycin nitroimidazole coupling molecule |
| WO2018157750A1 (en) * | 2017-02-28 | 2018-09-07 | 丹诺医药(苏州）有限公司 | New applications of rifamycin-nitroimidazole coupling molecules |
| CN108047250A (en) * | 2018-02-12 | 2018-05-18 | 丹诺医药(苏州）有限公司 | A kind of application of rifamycin-nitroimidazole coupling molecule |
| CN108047250B (en) * | 2018-02-12 | 2020-08-14 | 丹诺医药(苏州）有限公司 | Application of rifamycin-nitroimidazole coupled molecule |
| CN109464673A (en) * | 2019-01-08 | 2019-03-15 | 丹诺医药(苏州）有限公司 | Application and the preparation of rifamycin-quinolizine ketone coupling molecule and its salt |
| WO2024036578A1 (en) * | 2022-08-18 | 2024-02-22 | Tennor Therapeutics (Suzhou) Limited | Methods for preventing or treating h. pylori infection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104971061B (en) | 2017-11-07 |
| HK1215178A1 (en) | 2016-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104971061A (en) | Novel application of rifamycin-nitroimidazole coupling molecule | |
| Gardiner et al. | Clinical and microbiological characteristics of Eggerthella lenta bacteremia | |
| JP7460531B2 (en) | Methods and compositions for preventing microbial infections - Patents.com | |
| Sahal et al. | Multi drug resistance in strong biofilm forming clinical isolates of Staphylococcus epidermidis | |
| Donskey et al. | A polyclonal outbreak of predominantly VanB vancomycin-resistant enterococci in Northeast Ohio | |
| Dong et al. | Effects of sub-minimum inhibitory concentrations of ciprofloxacin on biofilm formation and virulence factors of Escherichia coli | |
| Bottega et al. | Evaluation of constitutive and inducible resistance to clindamycin in clinical samples of Staphylococcus aureus from a tertiary hospital | |
| Laport et al. | Antimicrobial activity of marine sponges against coagulase-negative staphylococci isolated from bovine mastitis | |
| Goncalves-Vidigal et al. | Stenotrophomonas maltophilia in cystic fibrosis: improved detection by the use of selective agar and evaluation of antimicrobial resistance | |
| Al-Saffar et al. | Isolation and characterization of Pseudomonas aeruginosa from Babylon province. | |
| Christensen et al. | Targeted screening of lactic acid bacteria with antibacterial activity toward Staphylococcus aureus clonal complex type 1 associated with atopic dermatitis | |
| Al‐Bakri et al. | Characterization of staphylococci sampled from diabetic foot ulcer of Jordanian patients | |
| Rusenova et al. | Comparison between some phenotypic and genotypic methods for assessment of antimicrobial resistance trend of bovine mastitis Staphylococcus aureus isolates from Bulgaria | |
| Bello-López et al. | Molecular characterization of microbial contaminants isolated from Umbilical Cord Blood Units for transplant | |
| Soroush et al. | Characterization of biofilm formation, antimicrobial resistance, and staphylococcal cassette chromosome mec analysis of methicillin resistant Staphylococcus hominis from blood cultures of children | |
| Talento et al. | Brevibacterium otitidis: an elusive cause of neurosurgical infection | |
| Okoye et al. | Detection and prevalence of methicillin and vancomycin resistant staphylococcus aureus among clinical isolates in ESUTH, Enugu State | |
| Temitope et al. | Antibiotic resistant pattern of bacteria isolated from faecal pellets of Supella longipalpa (Cockroach) found in Akungba Akoko, Ondo state, Nigeria | |
| Sullivan et al. | Antibacterial activity of synthetic fire ant venom: The solenopsins and isosolenopsins | |
| Zalas-Wiecek et al. | Influence of subinhibitory concentrations of cefotaxime, imipenem and ciprofloxacin on adhesion of Escherichia coli strains to polystyrene | |
| Nakano et al. | Survey of antimicrobial susceptibility patterns of the bacteria of the Bacteroides fragilis group isolated from the intestinal tract of children | |
| Kabli et al. | An epidemiological survey of extended-spectrum β-lactamases producing bacteria genotypes and the evaluation of the antimicrobial effect of Rhazya stricta leaf extract | |
| Eja et al. | Antibiogram studies and extended spectrum beta-lactamase activity profile of Salmonella-like species isolated from poultry soil of the University of Uyo, Nigeria | |
| Ghiaei et al. | Investigating the antagonistic effect of indigenous probiotics on carbapenem-resistant Pseudomonas aeruginosa strains | |
| Smith et al. | Cefsulodin chocolate blood agar: a selective medium for the recovery of Haemophilus influenzae from the respiratory secretions of patients with cystic fibrosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1215178 Country of ref document: HK |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1215178 Country of ref document: HK |